Substituted-methylene derivatives of ring e keto yohimbe alkaloids



United States Patent 3,250,768 SUBSTITUTED-METHYLENE DERIVATIVES 0F RING E KETO YOHIMBE ALKALOIDS Jay Donald Albright and Leon Goldman, Nanuet, N.Y., assignors to American Cyanamid Company, Stamford,

Conn., a corporation of Maine No Drawing. Filed Apr. 28, 1965, Ser. No. 451,627 29 Claims. (Cl. 260-240) This application is a continuation-in-pamt of our copendin-g application Serial No. 157,251, filed Dewmber 5, 1961, now abandoned.

This invention relates to novel substituted-methylene derivatives of ring E keto yohimbe alkaloids and, more particularly, is concerned with novel substituted-18-methylene derivatives of l7-ketoyohimbane which may be represented by the following general formula:

D LE

e l E wherein R is lower alkylthio, lower alkylamino, di(lower alkyl)amino, lower cycloalkylamino, anilino, substituted anilino, naphthylamino, pyrrolidino, piperidino, morpholino, pyridylamino, pyridylmethylamino, 4-substituted piperazino, 4-substituted piperidino, lower alkoxy(lower alkyl)amino and di(lower alkyl)amino(lower alkyl)- amino. Suitable lower alkylthio substituents contemplated by the .present invention are those having from 1 to 6 carbon atoms such as, for example, methylthio, ethylthio, isopropylthio, tert-butylthio, etc. Suitable lower alkylamino substituents contemplated by the present invention are those having from 1 to 6 carbon atoms such as et-hylamino, n-propylamino, n-butylamino, isobutylamino, etc. Suitable di(lower alkyl)amino substituents contemplated by the present invention are those having from 2 to 8 carbon atoms such as, for example, dimethylamino, diethylamino, di-n-propylamino, di-n-butylamino, (N-ethyl-N-hexyl)amino, etc. Suitable lowercycloalkylamino substituents may be cyclopropylamino, cyclopentylamino, cyclohexylamino, and the like. Suitable substituted anilino groups may be, for example, lower alkoxyanilino and lower alkylanilino wherein the lower alkoxy and lower alkyl groups are from 1 to 3 carbon atoms, haloanilino, acetamidoanilino and di(lower alkyl)aminoanilino wherein the di(lower alkyl)amino group is from 2 to 6 carbon atoms. Pyridylamino is exemplified by 2- pyridylamino, 3-pyridylarnino and 4-pyridylamino; whereas pyridylmet-hylamino is exemplified by Z-pyridylmethylamino, 3-pyridylmethylamino and 4-pyridylmethylamino. Suitable 4-substituted .piperazino substituents may be represented by the following formula:

wherein R is phenyl, lower alkyl of from 1 to 4 carbon 3,250,768 Patented May 10, 1966 atoms, lower alkoxycarbonyl of from 2 to 4 carbon atoms or a side chain of the formula:

CnHu 1 CnHznH CnHZn 1 wherein n is a whole number from -1 to 4. Suitable 4-substituted piperidino substituents may be represented by the following general formulae:

Curr,n 1

ohmn 1 CHzCHa R CHzCHz phenyl wherein n is a whole number from 1 to 4 and R" is cyano, acetamidomethyl, lower alkoxy of from 1 to 4 carbon atoms, lower alkanoyl of from 2 to 4 carbon atoms, lower alkanoyloxy of from 2 to 4 carbon atoms, lower alkoxycarbonyl of from 2 to 4 carbon atoms or a side chain of the formula:

' cureu 1 wherein n is a whole number from 1 to- 4. Suitable lower alkoxy(lower -alkyl)amino substituents contemplated by the present invention may be represented by the following formula: NHC H -OR" wherein R' is lower alkyl of from 1 to 3 carbon atoms and n is a whole number from 2 to 4. Suitable di(lower alkyl)-amino(lower alkyl)amino substituents contemplated -by the present invention may be represented by the following general formula:

whereinn is a whole number from 1 to 4.

The novel compounds of the present invention are, in general, white to tan crystalline solids, the free bases of which are soluble in organic solvents such as lower alkanols, chloroform, dimethylformamide, dioxane, pyridine and the like; and the salts of which are soluble in polar solvents such as water or lower alkanols.

The organic free bases of this invention form non-toxic acid addition salts with a variety of organic and inorganic salt-forming agents. Thus, acid-addition salts, formed by admixture of the organic free base with an acid, suitably in a neutral solvent, are formed with such acids as sulfuric, phosphoric, hydrochloric, hydrobromic, sulfamic, citric, lactic, tartaric, acetic, gluconic and the like. For purposes of this invention the free bases are equivalent to their non-toxic acid-addition salts.

The novel compounds of the present invention are valuable hypotensive agents of low toxicity and may be administered orally or parenterally. When so administered they have been found to exhibit hypotensive action in amounts ranging from about 25 to about 350 milligrams per kilogram of body weight. of the novel compounds of the present invention are also useful as anorexigenic agents and some have been found to exhibit tranquilizing action.

The novel compounds of the present invention may be prepared from yohimban-l7-one which has been described by Witkop, Ann. 554, 83 (1943). The first step in the synthesis of the novel compounds of the present invention In addition, some 'benzene was added 14 ml. of ethyl formate.

consists of the formylation of yohimban-l7-one with a lower alkyl iormate such as methyl or ethyl formate, in the presence of a suitable base such as. an alkali metal alkoxide, sodium hydride, sodamide, and the like. When yohimban-17-one is so treated, there is obtained IS-hyone intermediate may be treated with an appropriate 1 primary or secondary amine at temperatures of from 50 .C. to 100 C. for periods of time ranging from half an hour to 5 hours whereby the corresponding monosubstituted aminomethylene or disubstituted aminomethylene derivatives of yohimban-l7-one may be readily obtained.

The novel compounds of the present invention may be used as such but more preferably are used in the form of their non-toxic acid-addition salts which may be readily prepared as described hereinabove.

The invention will be described in greater detail in conjunction with the following specific examples.

Example I.Preparati0n 0 18-hydroxymethyleneyohimban-17-0ne To a cooled mixture of 10.0 g. of yohimban-17-one, 10.0 g. of sodium methoxide, and 300 ml. of sodium-dried The mixture was stirred under nitrogen at room temperature for 20 hours and poured onto a mixture of 300 g. of ice and 200 ml. of water. The organic layer was separated and washed with three, 100-ml. portions of 0.1 N sodium hydroxide. The basic washings and aqueous layer were combined and neutralized in the cold with acetic acid. Filtration afforded 9.4 g. of l8-hydroxymethyleneyohimban-l7-one hemihydrate as tan crystals, M.P. 140-l47 C. On standing in the cold overnight, the mother liquor gave an additional 1.8 g. of crystals. Recrystallization from methanol afiorded colorless needles, sintering to a glass at l45-148 C., M.P. 2072l0'C. (dec.).

Example 2.-Preparation of 18-hydr0xymethylene yohimban-U-one A mixture of 5.0 g. of yohimban-l7-one, 5.0 g. of

- sodium methoxide, 150 ml. of dry peroxide-free dioxane,

and 7.0 ml. of ethyl formate was stirred at room temperature under nitrogen for 21 hours. The mixture was neutralized with acetic acid and concentrated nearly to dryness. The residue was crystallized from aqueous methanol to yield 5.3 g. of lS-hydroxymethyleneyohimban-17- one hemihydrate as tan crystals, sintering to a glass at 145-154 C., M.P. 207210 C. (dec.).

Example 3.-Preparati0n of 18-n-butylthiomethyleneyohimban-J 7-0ne To a mixture of 0.663 g. of lS-hydroxymethyleneyohimban-17-one, 2.0 g. of magnesium sulfate, and 5.0 ml. of l-butanethiol was added ml. of acetic acid. The mixture was stirred at room temperature for 20 hours and filtered. The filtrate was partitioned between 50 ml.

of chloroform and. 100 ml. of 4 N sodium hydroxide.

After further chloroform extractions the combined organic layers were dried over magnesium sulfate and concentrated to give 0.660 g. of off-white crystals of 18-nbutylthiomethyleneyohimban 17 one. Recrystallization from acetone gave colorless crystals, M.P. 219 -222 C. (dec.).

Other compounds which can be prepared according to the above-described procedure are, for example:

1S-methylthiomethyleneyohimban-17-one, 1 S-ethylthiomethyleneyohim'b an- 1 7-one, l8-n-hexylthiomethyleneyohimbanl 7-one.

Example 4.--Preparation of 18-n-butylaminometlzylerzeyohimban-I 7-0ne A mixture of 8.29 g. of 18-hydroxymethyleneyohimban-l7-one, 60 ml. of butylamine and 100 ml. of ethanol was refluxed for 2 hours. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate. Chilling and filtering gave 7.1 g. of tan crystals, M.P. 237240 C. (dec.). The solid was dissolved in acetone-ethanol (:5) and the solution concentrated on a steam bath. Dilution with water and chilling gave 445 g. of l8-n-butylaminomethyleneyohimban-l7-one as light tan crystals, M.P. 244246 C. (dec.).

Other compounds which can be prepared according to the above-described procedure are, for example:

1S-methylaminomethyleneyohimban-l7-one, l8-ethylaminomethyleneyohimban-l 7-one, l8-isopropylaminomethyleneyohimban-l 7-one, 1 8-se c-butylaminomethyleneyohimban-17-one.

Example 5.-Preparaii0n of 18-is0butylamin0metlzyleneyohimban-17-0ne Amixture of 2.0 g. of 18-hydroxymethyleneyohim'ban- 17-one, 1.5 ml. of isobutylamine, and 30 ml. of ethanol was refluxed for 5 hours. After standing overnight, the solution was treated with activated charcoal, filtered, and the filtrate concentrated under reduced pressure to a brown glass. The glass was triturated with ml. of ether to give 1.42 g. of l8-isobutylaminomethyleneyohimban-17-one, containing one-fourth mole of water of crys tallization, as tan crystals, M.P. 210220 C. (dec.). Recrystallization from aqueous ethanol with the aid of activated charcoal attorded hygroscopic pale yellow needles, M.P. 222226 C. (dec.).

Other compounds which can be prepared according to the above-described procedure are, for example:

18-( l-ethylbutyl) aminomethylen'eyohimban-17-one, 18- (Z-methylamyl) aminomethyleneyohimban- 17 -one, 1 8-'( l ,1,2-trimethylpropyl)aminomethyleneyohimban- 17- one. Example 6.--Preparari0n of 1S-tert-butylaminomethyleneyohimbaml 7-0ne A mixture of 10.6 of 18-hydroxymethyleneyohimban- 17-one, 7.0 ml. of tert-butylamine and ml. of ethanol was refluxed for 5 hours. The solvent was removed under reduced pressure and the residue was dissolved in benzene. The solvent was removed under reduced pressure and the residue was triturated with methanol. The resulting suspension was chilled and filtered and the liltrate was concentrated under reduced pressure. The residue was triturated with ether and filtered to give 7.4 g. of tan crystals. Precipitation from ethyl acetate and recrystallization from aqueous acetone and acetone gave 2.84 g. of 1S-tert-butylaminomethyleneyohimban-l7-one 'as tan needles, M.P. 240-243 C. (dec.).

Example 7.Preparati0n of 18-diethylaminomethyleneyohim ban-1 7-one -A mixture of 8.29 g. of 18-hydroxymethyleneyohimban- 17-one, 5.0 ml. of diethylamine and 50 ml. of ethanol was refluxed for 1.5 hours. The solvent was removed under pressure. The residue was dissolved in acetone and the solvent removed under pressure. The residue was triturated with acetone and the mixture chilled and filtered to give 6.0 g. of tan crystals, M.P. 222-226 C. (dec.). Recrystallization from acetone with the aid of activated charcoal gave 2.90 g. of 18-diethylaminomethyleneyohimban-l7-one as tan crystals, M.P. 225228 C. (dec.).

Other compounds which can be prepared according to the above-described procedure are, for example:

l8-dimethylaminomethyleneyohimbanl7-one, 18-di-n-propylaminomethyleneyohimban-17-one.

Example 8.-Preparati0n 0f 18-di-n-pr0plaminomethyleneyalzimban-I 7-0ne A mixture of 8.29 g. of 18-hydroxyyohimban-17-one, 6.0 ml. of dipropylarnine and 100 ml. of ethanol was refluxed for 1.5 hours. The mixture was chilled and filtered to give 7.75 g. of yellow crystals, M.P. 241 245 C. (dec.). Recrystallization from ethanol gave 6.70 g. of 18-di-n-propylaminomethyleneyohirnban-17-one as tan crystals, M.P. 236-238 C. (dec.).

Other compounds which can be prepared according to the above-described procedure are, for example: 18-(N-methyl-N-amyl) aminomethyleneyohimban- 1 8- (N-ethyLN-hexyl) aminomethyleneyohimb anl7-one, 18- (N-ethyl-N-is obutyl) aminomethyleneyohimb anl7-one,

Example 9.-Preparati0n of 18-cyclohexylaminomezhyleneyohim'ban-l 7 -one A mixture of 8.29 g. of -1S-hydroxymethyleneyohimban-17-one, 6.0 ml. of cyclohexylamine and 100 ml. of ethanol was refluxed for 1.5 hours. The mixture was .chilled and filtered to give 5.6 g. of tan crystals, M.P.

275280 C. (dec.). Recrystallization from ethanol gave 3.95 g. of 18 cyclohexylam-inomethyleneyohimbanl7-one as tan crystals, M.P. 275 278 C. (dec.).

Other compounds which can be prepared according to the above-described procedure are, for example:

' 18-cyclopropylaminomethyleneyohimban-17-one,

18-cyclobutylaminomethyleneyohinrban-17-one,

18-cyclopentylaminomethyleneyohimbanl7-one,

18-(Z-methylcyclopenyl)aminomethyleneyohimban- 17-one.

Example 10.Preparati0n of 1-8-anilin0methyleneyolzimban-l7-one A mixture of 2.65 g. of l8-hydroxyme-thyleneyohim ban-17-o-ne, 0.90 ml. of aniline, and 40ml. of ethanol was refluxed for 3 hours. The mixture was cooled and filtered to give 2.55 g. of l8 anilinomethyleneyohimban- 17-one, containing one-fourth mole of water of crystallization, as yellow crystals, M.P. 305-310 C. (dec.). Recrystallization from N,N-dimethyltormamide afforded yellow crystals, M.P. 303 -3 07 C. (dec.).

Other compounds which can be prepared according to the above-described procedure are, for example:

18- (o-methoxyanilino methyleneyohirnban-17-one,

1 8- (p-ethoxyanilino methyleneyohimban-l 7-one,

18- (m-isopropoxyanilino methyleneyohimb an- 17 -one,

18 o-methylanilino met-hyleneyohimban-l7-one,

18-(m-ethylanilino methyleneyohimban-17-one,

18- p-isoamyl anilino methyleneyohimb an-17-one,

18* (o-chloro anilino) methyleneyohimban-l7-one,

18- (m-bromo anilino methyleneyohimban-17-one,

1 S-(p-iodoanilino) methyleneyohimban-17-one,

18- (m-acetamidoanilino methyleneyohimb an-l7-one,

l 8- (p-dimethylamino anilino methyleneyohimban- 17-one,

18-( l-naphthylamino)methyleneyohimban-17-one,

18- (Z-naphthylamino methyleneyohimb anl7-one.

Example 11.-Preparati0n of 18-pyrr0lidin0methyleneyohim ban-1 7-0ne A mixture of 2.0 g. of 18-hydr0xymethyleneyohimban- 17-one and 1.5 of distilled pyrrolidine in 30 ml. of absolute ethanol was refluxed for two and one-half hours. Cooling and filtration gave 1.49 g. of 18-pyrrolidinomethyleneyohimban-l7-one as yellow crystals, M.P.

306309 C. (the) (when inserted in an oil bath preheated to 150 C.). Recrystallization from absolute ethanolwith the aid of activated charcoal gave yellow crystals, M.P. 308 309? C. (dec.) (when inserted in an oil bath preheated to 305 C.).

Another compound which can be prepared according to the above-described procedure is 18-piperidinomethyleneyohimban-17-one.

Example 12.Preparati0n of 18-m0rph0lin0methyleneyohimban-I 7-0ne A mixture of 6.63 g. of 18hydroxymethyleneyohimban-17-one, 2.0 m1. of morpholine and ml. of ethanol was refluxed for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate-acetone (:5) was treated with activated carbon and filtered. The filtrate was chilled and filtered and the precipitate was washed with ethyl acetate to give 4.1 g. of orange amorphous solid. The solid was dissolved in dichloromethane and chromatographed over 3.5 g. of Florsil. Elution with dichloromethane and evaporation of the ol-uate igave -1.8 g. of 18-morpholinomethyleneyohim-ban 17-'one as a pale orange glass, sintering above C. and slowly melting with decomposition at l75l85 C.

Example 13.--Preparati0n of 18-(2-pyridylamin0) methyleneyohimban-l 7-0ne A mixture of 6.63 g. of 18-hydroxymethyleneyohimban-17-one, 2.07 g. of Z-aminopyridine and 75 ml. of ethanol was refluxed for 2 hours. Chilling and filtering gave 2.7 g. of yellow-brown crystals, M.P. 250-253 C. (dec.). The filtrate was concentrated under reduced pressure and the residue triturated with ethanol-ethyl acetate (1:1). Chilling and filtering gave 1.7 g. of yellow crystals, M.P. 258-261 C. (dec.). The two crops were combined, dissolved in ethanol-dichloromethane and the solution treated with activated carbon. The mixture was filtered and the filtrate concentrated to. give 1.8 g. of 18-(2-pyridylamino)methyleneyohimban-l7-one as yellow crystals, M.P. 262-264 C. (dec.).

Example 14.Preparati0n of 18-(3-pyridylamin0)methyleneyohim ban-1 7-0ne A mixture of 6.63 g. of l8-hydroxymethyleneyohimhan-17-one, 2.07 g. of 3-ami-nopyridine and 75 ml. of ethanol was refluxed for 2 hours. The mixture was chilled and filtered to give 5.5 g. of yellow crystals, M.P. 308311 C. (dec.). Concentration of the filtrate gave an additional 1.3 g. of product, M.P. 300-304 C. (dec.). The two crops of crystals were combined, dissolved in dichloromethane-acetone, and the solution con centrated. Chilling and filtering gave 3.0 g. of 18-(3- pyridylamino)methyleneyohimban-l7-one as yellow crystals, M.P. 311 -314 C. (dec.).

. Example I5.Preparazi0n of 18-(4-pyridylamino )methyleneyohimban-l 7-0ne A mixture of 6.63 g. of l8-hydroxymethyleneyohimban-17-one, 2.07 g. of 4-aminopyridine and 75 ml. of ethanol was refluxed for 2 hours. The dark solution was treated with activated carbon, filtered and the filtrate diluted with cyclohexane. The mixture was chilled and filtered and the filtered concentrated to a glass. The glass was dissolved in acetone and the solution diluted with water. Chilling and filtering gave 1.8 g. of product which was recrystallized from acetone to give 18 (4- pyridylamino)methyleneyohimban-l7-one as tan crystals, M.P. 306-309 C. (dec.).

Example J6.-Preparati0n of 18-(2-pyridylmethylamino)methyleneyohimban-1 7-0ne A mixture of 6.63 g. of 18-hydroxymethyleneyohim- :ban-17-one, 2.38 g. of 2-aminomethylpyridine and 75 ml. of ethanol was refluxed for 1.5 :hours. The solvent was removed under reduced pressure and the residue was dis- 7 solved in acetone. The solution was diluted with ethyl acetate and the insoluble gum which separated was removed by filtration. The filtrate was concentrated under reduced pressure to give a glass which was dissolved in 50 ml. of hot benzene. Dilution with ml. of cyclohexane gave a gum which on trituration, changed to a tan amorphous sol-id. The solid (7.0 g.) was dissolved in 100 ml. of ethyl acetate, treated with activated carbon and the mixture was filtered. The filtrate was diluted with 100 ml. of petroleum ether (B.-P. -60 C.) to give 5.5 g. of solid, changes to dark mass 125-13S C. The solid was purified by slurrying in 150 ml. of ethyl acetate, filtering from the insoluble solid and diluting the filtrate with 300 ml. of petroleum ether (B.P. 30-

Ch-illing and filtering gave 3.58 g. of 18-(2- pyridylmethylamino)methyleneyohimban-17-one as a tan amorphous solid, sinters above 100 C. to a red glass which slowly changes to a dark liquid.

Example 17.Preparation of 18-(3-pyriaylmethylamino) methyleneyohimban-l 7-one A mixture of 6.63 g. of 18-hydroxymethyleneyohimban- 17-one, 2.38 g. of 3-aminomethylpyridine and 75 ml. of

Example 1 8 .Prepaiati0n of 1 8-( 4 -pyridylmethylamino meihyleneyohimban-I 7-0ne A mixture of 6.63 g. of 1S-hydroxymethyleneyohimban- 17-one, 2.38 g. of 4-aminornethylpyridine and 75 ml. of ethanol was refluxed for 2 hours. The solvent was removed under reduced pressure and the residual glass dissolved in acetone. Chilling and filtering gave 4.68 g. of tan crystals, MLP, 160-170 C. (dec.). The crystals were dissolved in a mixture of 300 ml. of acetone and 15 ml. of methanol and the solution was treated with activated carbon, filtered and the filtrate concentrated. Chilling and filtering gave 3.1 g. of tan crystals, M.P. 176-180 C. (dec.) (with previous sintering). Recrystallization from acetone gave 1.95 g. of 18-(4-pyridylmethylamino)methyleneyohimban-l7-one as tan crys tals, M.P. 1{81-l85 C. (dec.) (with previous sintering).

Example 19.Preparati0n of l8-(4-etlzoxycarbonyl-1- piperazinyl -metkyleney0himban-l 7-0ne A mixture of 8.29 g. of 1S-hydroxymethyleneyohim- 18- (4methoxycarb onyl- 1 -pip erazinyl) methyleneyohimban-17-one,

18- (4-phenyl-1-piperazinyl) methyleneyohimban-l7-one,

18- 4-methyl- 1 -pip erazinyl) methyleneyohimban- 1 7-one,

18- (4-ethyl- L-piperazinyl) methyleneyohimbanl7-one,

1 8- (4-isobutyl- 1 -piperazinyl methyleneyohimb an-l7-one.

Example 20.Preparati0n 0 f 18- [4-(3-dimethylaminopropyl -I-piperazinylmethylene] yohimban-l 7-0ne A mixture of 5.0 g. of 18-hydroxymethyleneyohirnban- 17-one, 2.57 g. of l-(3-dimethylaminopropyl)piperazine and 50 ml. of ethanol was refluxed for 3 hours. The solvent was removed under reduced pressure and benzene 3 was added several times and the solvent removed after each addition under reduced pressure. The residue was dissolved in acetone and the solution was treated with activated carbon and filtered. ,The filtrate was diluted with heptane and filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in ether-dichloromethane (9:1) and filtered through a column of Florisil (30 g.). Elution with 600 ml. of etherdichlorornethane (9:1) and 400 ml. of dichloromethane, and concentration of the eluate, gave the roduct as an orange glass. Purification was accomplished by chromatography over 50 g. of Florisil with dichloromethane as the solvent. There was obtained 1.2 g. of 18-[4-(3-dimethylaminopropyl)-1 piperazinylmethylene]yohimban 17-one as a pale orange glass, sintering above C. and slowly melting at -140 C.

Other compounds which can be prepared according to the above-described procedure are, for example:

1,8-{4-(Z-diethylaminoethyl)-1-piperazinylmethy1ene] yohimban-17-one,

18-[4-(4-diisopropylarninobutyl)-1-piperazinylmethylene] yohimban- 17 -one,

18- [4-( 4-diethylamino-l -methylbutyl) -l-piperazinylmethylene] yohimban-17-one.

Example 2] .Preparatz'on 0 f 18- [4- (3-dimetlzylaminopropyl -pz'peridin0methylene] yohim ban-I 7-one A mixture of 6.63 g. of 1S-hydroxymethyleneyohimban-l7-one, 3.75 g. of 4-(3-dimethylaminopropyl)piperidine and 75 ml. of ethanol was refluxed for 2.5 hours. The solvent was removed under reduced pressure to give a glass and the glass was triturated with acetone to give crystals. Chilling and filtering gave 6.54 g. of product. Recrystallization from acetone gave 4.4 g. of 18- [4-(3-di- Inethylaminopropyl)piperidinomethylene] yohimban 17- one as tan crystals, M.P. 193 -196 C. (dec.).

Other compounds which can be prepared according to the above-described procedure are, for example:

1 8- [4-( Z-diethylaminoethyl piperidinornethylene] yohimban-17-one, 18- [4- (4-diisopropylaminobutyl) piperidinomethylene] yohimban-l7-one, l8- [4- (4-diethylaminol -methylbutyl) piperidinomethylene]yohimban-17-one, l8- [4-phenyl-4- 3-dimethylaminopropyl piperidinomethylene] y0himban-l7-one, 1 8- [4-phenyl-4- (Z-diethylaminoethyl) piperidinomethylene]yohirnban-l7-one. 18- [4-phenyl-4- (4-diisopropylaminobutyl) piperidinomethylene]yohimban-17-one, 18- [4-phenyl-4- (4-diethyl amino-l -methylbutyl piperidinomethylene]yohirnban-17-one. Example 22.--Preparati0n of l8-(3-methoxypropylamino) -methyleney0himban-1 7 -one A mixture of 6.63 g. of l8-hydroxymethyleneyohirnban-17-one, 2.23 g. of B-methoxypropylamine and 75 ml. of ethanol was refluxed for 2 hours. The solvent was removed under reduced pressure to give a glass which was dissolved in acetone and the solution chilled. Filtration gave 4.80 g. of tan crystals, M.P. 223-225 C. (dec.). Recrystallization from acetone gave 3.25 g. of 18-(3- methoxypropylarnino)methyleneyohimban-17-one as light tan crystals, M.P. 228-230 C. (dec.).

Other compounds which can be prepared according to the above-described procedure are, for example:

1 8-(2-methoxypropylamino methyleneyohimban-17-one,

li8-(3-isopropoxybutylamino)methyleneyohimb an-17- one,

1 8-(4-methoxybutylamino) methyleneyohimb an-l 7-one.

Example 23.Preparati0n of 18- (3-dimethylaminopropylamino) methyleneyohimban-l 7-0ne A mixture of 8.29 g. of lB-hydroxyrnethyleneyohimban- 17-one, 7.0 ml. of 3-dimethylaminopropylamine .and 100 ml. of ethanol was refluxed for 1.5 hours. The solvent was removed under reduced pressure and the residue was triturated with ether. Filtration gave 5.90 g. of tan solid. A second crop of 2.0 g. was obtained from the mother liquors. Several recrystallizations from acetone with the aid of activated charcoal give 3.2 g. of 18-(3-dimethylaminopropylamino)methyleneyohimban 17 one as tan crystals, MP. 201 203 C. (dec.).

Other compounds which can be prepared according to the above-described procedure are, for example:

18-(2-diethylaminoethylamino)methyleneyohimban- 17-one,

l 8- (4-diisopropylaminobutylamino) methyleneyohimb anl7-one,

1 8-(4-diethylamino-1-methylbuty1amino) methyleneyohimban-l7-one.

Example 24.Preparati0n of 18-(4-acetamid0methyl-4- phenylpiperz'dino)methyleneyohimban-17-0ne l8-(4-cyano-4-phenylpiperidino)methyleneyohimbanl7-one, 18-(4-ethoxycarbonyl-4-phenylpiperidino)methyleneyohimban-l7-one, 18-(4-acetyl-4-phenylpiperidino)methyleneyohimban- 17-one, 1 8- (4-ethoxy-4-phenylpiperidino )methyleneyohimbanl7-one, l8-(4-acetoxy-4-phenylpiperidino)methyleneyohimbanl7-one.

What is claimed is: 1. A member selected from the group consisting of a compound of the formula:

wherein R is selected from the group consisting of lower alkylthio; lower alkylamino; di(lower alkyl) amino; lower cycloalkylamino; anilino; lower alkoxyanilino; lower alkylanilino; haloanilino; acetamidoanilino; di(lower alkyl)aminoanilino; naphthylamino; pyrrolidino; piperidino; morpholino; pyridylamino; pyridylmethylamino; 4- substituted piperazino of the formula:

wherein R is selected from the group consisting of phenyl, lower alkyl, lower alkoxycarbonyl and a side chain of the formula:

CnH2n+ l CnH2n-N nH2u+ 1 wherein n is a whole number from 1 to 4; 4-substituted piperidino of the formulae:

CHnC Hg omci phenyl wherein n is a whole number from 1 to 4 and R" is selected from the group consisting of cyano, acetamidomethyl, lower alkoxy, lower alkanoyl, lower alkanoyloxy, lower alkoxycarbonyl and a side chain of the formula:

C Ha -N CnHml 1 wherein n is a whole number from 1 to 4; lower alkoxy (lower alkyl)amino of the formula:

wherein R is lower alkyl and n is a whole number from 2 to 4 and di(lower alkyl) amino(lower alkyl)amino.

. 18-n-butylthiomethyleneyohimban-17-one. 18-n-butylaminomethyleneyohimban-17-one.

1 8-isobutylaminomethyleneyohimban-17-one. 18-diethylaminomethyleneyohimban-17-one. 18-di-n-propylaminomethyleneyohimban-17-one. 18-cyclohexylaminomethyleneyohimban-17-one.

18-anilinornethyleneyohimban-17-one. l8-pyrrolidinomethyleneyohimban-17-one.

10. 18-morpholinomethyleneyohirnban-17-one.

11. l8-(2-pyridylamino)methyleneyohimban-l7-one.

12. 18-(4-pyridylamino)methyleneyohimban-17-one.

13. lS-(Z-pyridylmethylamino)methyleneyohimban- 17-one.

14. 18-(3-pyridylmethylamino)methyleneyohimbanl7-one.

15. 18-(4-ethoxycarbonyl-1-piperazinyl)methyleneyohimban-l7-one.

16. 18-[4-(3-dimethylaminopropyl)-1-piperaziny1- methylene]yohimban 17-one.

17. 18-[4-(3-dimethylaminopropyl)piperidinomethylene1yohimbau-17-one.

18. 18-(3-methoxypropylamino)methyleneyohimban- 17-one.

19. 18-(3-dimethylaminopropylamino)methyleneyohimban-17-one.

20. l8-(4-acetamidomethyl-4-phenylpiperidino)- methyleneyohimban-l7-one.

s m a No references cited.

WALTER A. MODANCE, Primary Examiner. J. A. PA'I'IEN, Assistant Examiner. 

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA: 